Relative depolarization of the cell membrane has been reported during carcinogenesis, possibly due to changes in the ratio of sodium to potassium as can occur during activation of oncogenes. It is not known whether cell membrane depolarization is a cause or consequence of cell growth; but in either case, it is reasonable to expect a corresponding change in the ionic composition of the interstitial fluid that might, in turn, be detected as a transmural or transepithelial potential difference. In a preliminary study, the mean membrane potential of breast-tissue cells was found to be significantly depolarized in patients with infiltrating ductal carcinoma, compared with patients having benign lesions. In other studies, we evaluated the possibility that measurements of the potential difference on the skin could reveal the presence of breast cancer. A total of 110 women who each had a palpable breast mass were studied, consisting of 81 patients with benign disease and 29 with cancer (mostly ductal carcinoma). The tumor site was 4.0 (4.5) mV positive, on average, with respect to the ipsilateral (contralateral) control sites when the mass was a cancer (determined by biopsy) (P < 0.05 in both cases); the tumor site was indistinguishable from the control sites when the tumor was benign. The results were not related to age or menstrual cycle. In this study, the utility of potential-difference measurements will be further tested after incorporating improvements suggested by the results of the initial studies. After measurement of potential difference, the cell membrane potentials will be determined using biopsy specimens from the same patients to evaluate the hypothesized relationship with the potential measurements. To accomplish these objectives, we will determine: 1. the sensitivity and specificity of measurements of potential difference for the diagnosis of breast cancer, using biopsy results as the standard of comparison; 2. whether the membrane potential in cells from breast biopsies of patients having malignant tumors differs significantly from the membrane potential of cells in benign lesions, and whether any such differences are correlated with the potential measurements. The ultimate objective of these studies is to develop and validate a method for diagnosing breast cancer that does not require use of ionizing radiation (mammography), but the method could have important implications for the detection of other forms of cancer.